An appropriate beta cell mass is pivotal for the maintenance of glucose homeostasis. Both insulin and IGF-1 are important in regulation of beta cell growth and function (reviewed in ref. 2). To define the roles of these hormones directly, we created a mouse model lacking functional receptors for both insulin and IGF-1 only in beta cells (betaDKO), as the hormones have overlapping mechanisms of action and activate common downstream proteins. Notably, betaDKO mice were born with a normal complement of islet cells, but 3 weeks after birth, they developed diabetes, in contrast to mild phenotypes observed in single mutants. Normoglycemic 2-week-old betaDKO mice manifest reduced beta cell mass, reduced expression of phosphorylated Akt and the transcription factor MafA, increased apoptosis in islets and severely compromised beta cell function. Analyses of compound knockouts showed a dominant role for insulin signaling in regulating beta cell mass. Together, these data provide compelling genetic evidence that insulin and IGF-I-dependent pathways are not critical for development of beta cells but that a loss of action of these hormones in beta cells leads to diabetes. We propose that therapeutic improvement of insulin and IGF-I signaling in beta cells might protect against type 2 diabetes.

Insulin and insulin-like growth factor I (IGF-I) are ubiquitous hormones that regulate growth and metabolism of most mammalian cells, including pancreatic ␤-cells. In addition to being an insulin secretagogue, glucose regulates proliferation and survival of ␤-cells. However, it is unclear whether the latter effects of glucose occur secondary to autocrine activation of insulin signaling proteins by secreted insulin. To examine this possibility we studied the effects of exogenous glucose or insulin in ␤-cell lines completely lacking either insulin receptors (␤IRKO) or insulin receptor substrate 2 (␤IRS2KO). Exogenous addition of either insulin or glucose activated proteins in the insulin signaling pathway in control ␤-cell lines with the effects of insulin peaking earlier than glucose. Insulin stimulation of ␤IRKO and ␤IRS2KO cells led to blunted activation of phosphatidylinositol 3-kinase and Akt kinase, while surprisingly, glucose failed to activate either kinase but phosphorylated extracellular signal-regulated kinase. Control ␤-cells exhibited low expression of IGF-1 receptors compared to compensatory upregulation in ␤IRKO cells. The signaling data support the slow growth and reduced DNA and protein synthesis in ␤IRKO and ␤IRS2KO cells in response to glucose stimulation. Together, these studies provide compelling evidence that the growth and survival effects of glucose on ␤-cells require activation of proteins in the insulin signaling pathway.Pancreatic islet ␤-cell regeneration and function are regulated by multiple stimuli, including nutrients, hormones, and growth factors acting via diverse intracellular signaling pathways (4, 43). Glucose is the primary regulator of insulin secretion and insulin biosynthesis, and its effects on growth and survival have been suggested to occur by activation of insulin receptor substrate 2 (IRS-2), a protein in the insulin/insulinlike growth-factor I (IGF-I) signaling pathway (40,45). Indeed, over the last decade most components in the insulin signaling pathway have been identified in murine and human pancreatic ␤-cells (1, 4, 17, 36), and their cross talk with other signaling pathways in ␤-cells is being systematically unraveled using genetic approaches in mice (reviewed in references 4 and 31). For example, insulin signaling has been reported to regulate many effects in ␤-cells that are also promoted by glucose, such as enhancing insulin gene expression, insulin secretion, proinsulin biosynthesis, and cell cycle progression (25,(28)(29)(30)38). Considering the similar effects of insulin and glucose in ␤-cells that occur by activation of largely similar proteins in the insulin/IGF-I signaling pathway, it is unclear whether the effects of glucose require activation of insulin receptors via secreted insulin.Examination of the independent effects of glucose versus insulin on ␤-cell function in vivo is limited by a lack of suitable mouse models. Further, the difficulty in separating the downstream effects of exogenous glucose from those of exogenous insulin in cultured ␤-cells ...

OBJECTIVE-Liver-specific inactivation of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) by a dominant-negative transgene (L-SACC1 mice) impaired insulin clearance, caused insulin resistance, and increased hepatic lipogenesis. To discern whether this phenotype reflects a physiological function of CEACAM1 rather than the effect of the dominant-negative transgene, we characterized the metabolic phenotype of mice with null mutation of the Ceacam1 gene (Cc1RESEARCH DESIGN AND METHODS-Mice were originally generated on a mixed C57BL/6x129sv genetic background and then backcrossed 12 times onto the C57BL/6 background. More than 70 male mice of each of the Cc1 Ϫ/Ϫ and wild-type Cc1 ϩ/ϩ groups were subjected to metabolic analyses, including insulin tolerance, hyperinsulinemic-euglycemic clamp studies, insulin secretion in response to glucose, and determination of fasting serum insulin, C-peptide, triglyceride, and free fatty acid levels. RESULTS-Like L-SACC1, Cc1Ϫ/Ϫ mice exhibited impairment of insulin clearance and hyperinsulinemia, which caused insulin resistance beginning at 2 months of age, when the mutation was maintained on a mixed C57BL/6x129sv background, but not until 5-6 months of age on a homogeneous inbred C57BL/6 genetic background. Hyperinsulinemic-euglycemic clamp studies revealed that the inbred Cc1 Ϫ/Ϫ mice developed insulin resistance primarily in liver. Despite substantial expression of CEACAM1 in pancreatic ␤-cells, insulin secretion in response to glucose in vivo and in isolated islets was normal in Cc1 Ϫ/Ϫ mice (inbred and outbred strains). CONCLUSIONS-Intact insulin secretion in response to glucose and impairment of insulin clearance in L-SACC1 and Cc1Ϫ/Ϫ mice suggest that the principal role of CEACAM1 in insulin action is to mediate insulin clearance in liver.